A pilot randomized controlled trial to compare the effectiveness of two 14-day primaquine regimens for the radical cure of vivax malaria in South India

Abstract

BackgroundRadical cure of Plasmodium vivax malaria requires treatment with a blood schizonticide and a hypnozoitocide (primaquine) to eradicate the dormant liver stages. There has been uncertainty about the operational effectiveness and optimum dosing of the currently recommended 14-day primaquine (PQ) course.MethodsA two centre, randomized, open-label, two arm study was conducted in South India. Patients were randomized to receive either high dose (0.5 mg base/kg body weight) or conventional dose (0.25 mg/kg) PQ for 14 days. Plasma concentrations of PQ and carboxyprimaquine (CPQ) on the 7th day of treatment were measured by reverse phase high performance liquid chromatography. Study subjects were followed up for 6 months. Recurrent infections were genotyped using capillary fragment length polymorphism of two PCR-amplified microsatellite markers (MS07 and MS 10).ResultsFifty patients were enrolled. Baseline characteristics and laboratory features did not differ significantly between the groups. Mean age of the study population was 42 ± 16.0 years. Recurrences 80–105 days later occurred in 4 (8%) patients, two in each the groups. All recurrences had the same microsatellite genotype as that causing the index infection suggesting all were relapses. One relapse was associated with low CPQ concentrations suggesting poor adherence.ConclusionsThis small pilot trial supports the effectiveness of the currently recommended lower dose (0.25 mg/kg/day) 14 day PQ regimen for the radical cure of vivax malaria in South India.Trial registration Clinical Trials Registry-India, CTRI/2017/03/007999. Registered 3 March 2017, http://ctri.nic.in/Clinicaltrials/regtrial.php?modid=1&compid=19&EncHid=82755.86366.

Primaquine at alternative dosing schedules for preventing relapse in people withPlasmodium vivaxmalaria

“…Four trials were conducted in South America: one in Colombia (Carmona‐Fonseca 2009 COL), one in Brazil (Abdon 2001 BRA), and two in Peru (Solari‐Soto 2002 PER; Durand 2014 PER). Five trials were conducted in Asia: one in Pakistan (Leslie 2008 PAK), one in Thailand (Bunnag 1994 THA), and three in India (Rajgor 2014 IND; Pareek 2015 IND; Saravu 2018 IND). All nine trials included data for adults, and four trials included children under the age of 10 years (Solari‐Soto 2002 PER; Leslie 2008 PAK; Carmona‐Fonseca 2009 COL; Durand 2014 PER).…”

“…Only one trial included people with G6PD deficiency (Leslie 2008 PAK). Six trials excluded people with G6PD deficiency (Bunnag 1994 THA; Carmona‐Fonseca 2009 COL; Durand 2014 PER; Rajgor 2014 IND; Pareek 2015 IND; Saravu 2018 IND), and two trials did not specify whether or not people with G6PD deficiency were included (Abdon 2001 BRA; Solari‐Soto 2002 PER). All of the trials used microscopy for diagnosis of parasitaemia.…”

“…All of the trials used microscopy for diagnosis of parasitaemia. Four trials carried out PCR genotyping of vivax parasitaemia as well (Durand 2014 PER; Rajgor 2014 IND; Pareek 2015 IND; Saravu 2018 IND).…”

“…Four trials described adequate methods of treatment randomization and were judged to be at low risk of selection bias (Durand 2014 PER; Rajgor 2014 IND; Pareek 2015 IND; Saravu 2018 IND). We assessed one trial as being at high risk of bias as it used two different methods of randomization depending on location, using house numbers or sequential patient numbers (Leslie 2008 PAK).…”

“…c Downgraded once for imprecision: wide CIs ‐ range of 58% reduction in malaria recurrences at 6 months with high‐standard 14‐day course of primaquine to 43% increase in number of malaria recurrences. d Downgraded once for indirectness: only one trial conducted in India in G6PD‐normal adults (Saravu 2018 IND). e Downgraded once for risk of bias: no blinding, high rate of loss to follow‐up.…”